Magnetohyperthermia for treatment of gliomas: experimental and clinical studies

Silva, André César da; Oliveira, Tiago Ribeiro; Mamani, Javier Bustamante; Malheiros, Suzana Mária Fleury; Pavon, Lorena Favaro; Sibov, Tatiana Taís; Amaro Junior, Edson; Gamarra, Lionel Fernel

doi:10.1590/S1679-45082010RW1757

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Review • Einstein (São Paulo) 8 (3) • Jul-Sep 2010 • https://doi.org/10.1590/S1679-45082010RW1757 copy

Magnetohyperthermia for treatment of gliomas: experimental and clinical studies

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Gliomas comprise a group of heterogeneous primary tumors of the central nervous system that originate from glial cells. Malignant gliomas account for the majority of primary malignant CNS tumors and are associated with high morbidity and mortality. Glioblastoma is the most frequent malignant glioma, and despite recent advances in diagnosis and new treatment options, its prognosis remains dismal. New opportunities for the development of effective therapies for malignant gliomas are urgently needed. Magnetohyperthermia consists of heat generation in the region of the tumor through the application of magnetic nanoparticles subjected to an alternating magnetic field and has shown positive results in both preclinical and clinical assays. The aim of this review was to assess the relevance of hyperthermia induced by magnetic nanoparticles in treating gliomas and to describe possible variations of the technique and its implication in the effectiveness of treatment. An electronic search in the literature of articles published from January 1990 to November 2009 was performed, in databases ISI Web of Science and PubMed, and after screening according to the inclusion criteria, 11 articles were selected. Animal models showed that magnetohyperthermia was effective in promoting tumor cell death and reducing tumor mass or increasing survival of the animals. One clinical study demonstrated that magnetohyperthermia could be applied safely and with few adverse effects. Some studies suggested that mechanisms of cell death, such as apoptosis, necrosis, and antitumor immune response were triggered by magnetohyperthermia. Based on these data, it was concluded that the technique proved to be effective in most experiments, and improvement of the nanocomposites, as well as of the alternating magnetic field equipment, can contribute towards establishing magnetohyperthermia as a promising tool to treat malignant gliomas.

Keywords:
Glioma; Central nervous system neoplasms; Hyperthermia, induced; Nanoparticles; Magnetics; Models, animal

Authors	Tumor cell line	Animal	Gender	Age (weeks-old)	Site of injection	Minimum inoculation (cells)	Days to initiate MHT after inoculation of tumor cells	Size of tumor (mm)/shape
Yanase M et al.(¹⁰10. Yanase M, Shinkai M, Honda H, Wakabayashi T, Yoshida J, Kobayashi T. Intracellular hyperthermia for cancer using magnetite cationic liposomes: ex vivo study. Jpn J Cancer Res. 1997;88(7):630-2.)	T-9	Fisher rat F-344	Female	7-8	Subcutaneous (left femoral region)	1 × 10⁶	-	3/ellipsoidal
Yanase M et al.(¹¹11. Yanase M, Shinkai M, Honda H, Wakabayashi T, Yoshida J, Kobayashi T. Intracellular hyperthermia for cancer using magnetite cationic liposomes: an in vivo study. Jpn J Cancer Res. 1998;89(4):463-9.)	T-9	Fisher rat F-344	Female	6-7	Subcutaneous (left femoral region)	1 × 10⁷	11	13-18/ellipsoidal
Yanase M et al.(¹²12. Yanase M, Shinkai M, Honda H, Wakabayashi T, Yoshida J, Kobayashi T. Antitumor immunity induction by intracellular hyperthermia using magnetite. Jpn J Cancer Res. 1998;89(7):775-82.)	T-9	Fisher rat F-344	Female	6-7	Subcutaneous (left and right femoral region)	1 × 10⁷	11	13-18/ellipsoidal
Shinkai M et al.(¹³13. Shinkai M, Yanase M, Suzuki M, Honda H, Wakabayashi T, Yoshida J, et al. Intracellular hyperthermia for cancer using magnetite cationic liposomes. J Magn Magn Mater. 1999;194(1-3):176-84.)	T-9	Fisher rat F-344	Female	6-7	Subcutaneous (left and right femoral region)	1 × 10⁷	11	13-18/ellipsoidal
Ito A et al.(¹⁵15. Ito A, Shinkai M, Honda H, Kobayashi T. Heat-inducible TNF-alpha gene therapy combined with hyperthermia using magnetic nanoparticles as a novel tumor-targeted therapy. Cancer Gene Ther. 2001;8(9):649-54.)	U-251-SP	Athymic mice	Female	4	Right flank	3 × 10⁷	-	8 (-)
Le B et al.(¹⁴14. Le B, Shinkai M, Kitade T, Honda H, Yoshida J, Wakabayashi T, et al. Preparation of tumor-specific magnetoliposomes and their application for hyperthermia. J Chem Eng Japan. 2001;34(1):66-72.)	U251-SP	KSN-nu/nu mice	Female	4	Subcutaneous (femoral region)	-	21	10/ellipsoidal
Ohno T et al.(¹⁶16. Ohno T, Wakabayashi T, Takemura A, Yoshida J, Ito A, Shinkai M, et al. Effective solitary hyperthermia treatment of malignant glioma using stick type CMC-magnetite. In vivo study. J Neurooncol. 2002;56(3):233-9.)	T-9	Fisher rat F-344	Female	4	Right cerebral hemisphere	5 × 10⁶	8	-
Ito A et al.(⁹9. Ito A, Shinkai M, Honda H, Yoshikawa K, Saga S, Wakabayashi T, et al. Heat shock protein 70 expression induces antitumor immunity during intracellular hyperthermia using magnetite nanoparticles. Cancer Immunol Immunother. 2003;52(2):80-8.)	T-9	Fisher rat F-344	Female	6	Subcutaneous space	1 ×10⁷	-	10 (-)
Jordan A et al.(⁸8. Jordan A, Scholz R, Maier-Hauff K, van Landeghem FK, Waldoefner N, Teichgraeber U, et al. The effect of thermotherapy using magnetic nanoparticles on rat malignant glioma. J Neurooncol. 2006;78(1):7-14.)	RG-2	Fisher rat F-344	Male	-	Thalamic region	1 × 10⁵	4	3-4/circular

	Groups/number of animals per group	Tumor size (mm)	Amount of Fe₃O₄ administered	Time to apply AMF after administration of Fe₃O₄ (h)	^* * Maximum temperature achieved during AMF application. Maximum therapeutical temperature (°C)	Time to achieve therapeutical temperature (min)	Duration of AMF application per session (min)	Number of AMF applications per group	Methods to assess efficacy of MHT therapy	Combined Therapy
Yanase M et al.(¹⁰10. Yanase M, Shinkai M, Honda H, Wakabayashi T, Yoshida J, Kobayashi T. Intracellular hyperthermia for cancer using magnetite cationic liposomes: ex vivo study. Jpn J Cancer Res. 1997;88(7):630-2.)	3/5	3	3 µg/150 µl	N/I	≅ 45	20	60	1 and 3	“Tumor take”	No
Yanase. M et al. (¹¹11. Yanase M, Shinkai M, Honda H, Wakabayashi T, Yoshida J, Kobayashi T. Intracellular hyperthermia for cancer using magnetite cationic liposomes: an in vivo study. Jpn J Cancer Res. 1998;89(4):463-9.)	4/10-13	13-18	3 mg/400 µl	24	≅ 44	15	30	1, 2 and 3	Berlin blue (Prussian blue) counter-stained with Kernechtrot or HE, “Tumor volume”	No
Yanase M et al.(¹²12. Yanase M, Shinkai M, Honda H, Wakabayashi T, Yoshida J, Kobayashi T. Antitumor immunity induction by intracellular hyperthermia using magnetite. Jpn J Cancer Res. 1998;89(7):775-82.)	2/8, 21	13-18	3 mg/400 µl	24	≅ 45	10	30	3	“Tumor volume”, HE, Immunohistochemistry (CD3, CD4, CD8 and NK)	No
Shinkai M et al.(¹³13. Shinkai M, Yanase M, Suzuki M, Honda H, Wakabayashi T, Yoshida J, et al. Intracellular hyperthermia for cancer using magnetite cationic liposomes. J Magn Magn Mater. 1999;194(1-3):176-84.)	4/5	13-18	3 mg /400 µl	N/I	≅ 44	15	30	1, 2 and 3	HE, Immunohistochemistry (CD3, CD4, CD8 and NK)	No
Le B et al.(¹⁴14. Le B, Shinkai M, Kitade T, Honda H, Yoshida J, Wakabayashi T, et al. Preparation of tumor-specific magnetoliposomes and their application for hyperthermia. J Chem Eng Japan. 2001;34(1):66-72.)	2/5	10	0.5 mg/100 µl	24	≅ 43	20	30	3	Immunohistochemistry (G22–FML)	No
Ito A et al.(¹⁵15. Ito A, Shinkai M, Honda H, Kobayashi T. Heat-inducible TNF-alpha gene therapy combined with hyperthermia using magnetic nanoparticles as a novel tumor-targeted therapy. Cancer Gene Ther. 2001;8(9):649-54.)	4/5	8	3 mg/200 µl	24	≅ 46	3	30	1	Immunohistochemistry (TNF-α), TNF - α ELISA	Gene therapy (TNF-α)
Ohno T et al.(¹⁶16. Ohno T, Wakabayashi T, Takemura A, Yoshida J, Ito A, Shinkai M, et al. Effective solitary hyperthermia treatment of malignant glioma using stick type CMC-magnetite. In vivo study. J Neurooncol. 2002;56(3):233-9.)	3/5	N/I	N/I	24	≅ 44.4	N/I	30	1 and 3	HE, Prussian blue, “Survival rate”, Berlin blue counter-stained with Kernechtrot or HE	No
Ito A et al.(⁹9. Ito A, Shinkai M, Honda H, Yoshikawa K, Saga S, Wakabayashi T, et al. Heat shock protein 70 expression induces antitumor immunity during intracellular hyperthermia using magnetite nanoparticles. Cancer Immunol Immunother. 2003;52(2):80-8.)	4/5	10	3 mg /400 µl	24	≅ 45	4	30	1, 2 and 3	HE, Immunohistochemistry (HSP70), TUNEL	Gene therapy (HSP 70)
Jordan A et al.(⁸8. Jordan A, Scholz R, Maier-Hauff K, van Landeghem FK, Waldoefner N, Teichgraeber U, et al. The effect of thermotherapy using magnetic nanoparticles on rat malignant glioma. J Neurooncol. 2006;78(1):7-14.)	10/12	3-4	1.8 mol/l 2.0 mol/l	0	39.43-47	10	40	1	Prussian blue/Immunohistochemistry (PCNA and GFAP)	No

Patients	Sex	Age (years)	Glioblastoma	First-line treatment	Second-line treatment	Amount of magnetic fluid instilled (ml)	Intratumoral temperature (°C)	Survival after MHT (months)	Brain mass (g)	Autopsy (^* * All lesions had aspect of solid tumor with necrotic and hemorrhagic areas, in addition to multifocal deposition of magnetic nanoparticles predominantly in necrotic regions; the morphological and histological aspects were similar among patients, who expressed GFAP in one-third of tumor cells and S100 in many cells; )	Mean mitosis rate/proliferation (^† † There was no difference between patients 1 and 3 regarding mitosis rate and proliferation; )
P1	Male	41	Left frontoparietal	Surgery, radiation therapy and chemotherapy	Radiation therapy and six MHT sessions	4.5	49.5	7.9	1,780	Signs of transtentorial and subfalcial herniation	1.2 ± 0.1/0.0625 µm²/10.3 ± 1.4%
P2 (^‡ ‡ The patient died due to pneumonia 14 days after instillation of magnetic fluid. )	Male	57	Left temporo-occipital	Not treated	-	4.2	-	-	1,610	Signs of transtentorial herniation	1.3 ± 0.3/0.0625 µm²/15.3 ± 2.5%
P3	Male	69	Left temporal	Surgery and radiation therapy	Chemotherapy and six MHT sessions	4.6	65.6	2.1	1,640	Generalized edema with transtentorial and tonsillar herniation	1.2 ± 0.3/0.0625 µm²/11.8 ± 1.8%

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[1] Corresponding author: Lionel Fernel Gamarra – Instituto Israelita de Ensino e Pesquisa Albert Einstein – Avenida Albert Einstein, 627/701 – Morumbi – CEP 05651-901 – São Paulo (SP), Brasil – e-mail: lgamarra@einstein.br